Deciphering the Tumor Microenvironment in Prostate Cancer: A Focus on the Stromal Component

Abstract

Prostate cancer progression is significantly affected by its tumor microenvironment, in which mesenchymal cells play a crucial role. Stromal cells are modified by cancer mutations, response to androgens, and lineage plasticity, and in turn, engage with epithelial tumor cells via a complex array of signaling pathways and ligand-receptor interactions, ultimately affecting tumor growth, immune interaction, and response to therapy. The metabolic rewiring and interplay in the microenvironment play an additional role in affecting the growth and progression of prostate cancer. Finally, therapeutic strategies and novel clinical trials with agents that target the stromal microenvironment or disrupt the interaction between cellular compartments are described. This review underscores cancer-associated fibroblasts as essential contributors to prostate cancer biology, emphasizing their potential as prognostic indicators and therapeutic targets.

Keywords: cancer-associated fibroblasts (CAFs); castration-resistant prostate cancer (CRPC); mesenchymal cells; prostate cancer (PCa); tumor microenvironment (TME).

Figure 1

Interaction dynamics between epithelial and stromal/mesenchymal components of the prostate during various stages of development and adulthood. (A) Developing fetal prostate: during fetal prostate development, epithelial cells and embryonic mesenchyme engage in reciprocal interactions mediated by morphogens and mitogens. (B) Adult prostate: in the adult prostate, stromal cells maintain tissue homeostasis through continuous interactions with the epithelial cells. Testosterone regulates these interactions. Homeostatic feedback mechanisms between the epithelium and stroma are essential for preserving the quiescent state of the prostate tissue. Adapted from [29].

Figure 2

Definition of the stromal microenvironment in murine prostate cancer GEMMs and projections on human tumors. scRNA sequencing studies in wild-type (WT) and mutant (MT) mouse prostates identify mesenchymal cell clusters [14]. Top Panel: Among the identified cell types are smooth muscle cells, myofibroblasts, and pericytes. The fibroblast populations are further divided into seven distinct clusters, which overlap with mesenchymal cell clusters M1 and M2, previously described in WT Bl6 mouse [16]. Bottom Panel: In mutants, specific mesenchymal clusters are shown, which include myofibroblasts, clusters common to all GEMM models, AR positive and AR negative stromal clusters. Some clusters projected into human prostate cancer are conservation across species [14]. The yellow circle indicates the positions of the prostates in both mouse and human models. The arrows illustrate the distribution of stromal clusters in both species.

Figure 3

Schematic overview of key signaling pathways in PCa states and the crosstalk with CAFs. This figure illustrates the major signaling pathways involved in three distinct forms of PCa: castration-sensitive prostate cancer (CSPC), castration-resistant prostate cancer (CRPC), neuroendocrine prostate cancer (NEPC), and the interaction between tumor epithelial cells and CAFs.